Metabolic reprogramming in saliva of mice treated with the environmental and tobacco carcinogen dibenzo[def, p]chrysene

Abstract The goal of this study is to develop a non-invasive approach for early detection of oral squamous cell carcinoma (OSCC) using our established mouse model that faithfully recapitulates the human disease. We present for the first time a comparative metabolomic profiling of saliva samples of the tobacco smoke constituent, dibenzo[ def , p ]pyrene, (DB[ a , l ]P) vs. DMSO (control)-treated mice using an established and highly sensitive LC-MS/MS approach. DB[ a , l ]P was administered by topical application into the mouse oral cavity (25 µmol, 3x week for 6 weeks) and saliva was collected 24 h after the last dose of carcinogen administration. Using an untargeted metabolomics approach (negative and positive modes), we found that DB[ a , l ]P differentially altered several metabolites known to be involved in the carcinogenesis process when compared to DMSO. Of particular significance, we found that DB[ a , l ]P significantly enriched the levels of phosphatidic acid, known to bind and activate mTORC which can enhance proliferation and promote carcinogenesis. Pathway enrichment analysis revealed that DB[ a , l ]P altered two major lipid metabolism pathways (phospholipid biosynthesis and glycerolipid metabolism). Collectively, our results using saliva as a safe and non-invasive approach, provide additional mechanistic insights on DB[ a , l ]P-induced OSCC and potential biomarkers for early detection and an opportunity for cancer interception via reprogramming lipid metabolism.